P.217 - Stabilized next-generation recombinant human acid alpha-glucosidase ATB200 clears accumulated glycogen and reverses cellular dysfunction to increase muscle strength in a mouse model of Pompe disease

Abstract

Pompe disease is a rare inherited metabolic disease of impaired lysosomal glycogen metabolism due to acid alpha-glucosidase (GAA) deficiency, which leads to progressive muscle weakness. Our biochemical and histologic evaluation of muscles of Gaa knockout (KO) mice revealed extensive cellular dysfunction, as evidenced by pronounced autophagy and lysosomal proliferation and potentially altered membrane repair. To date, enzyme replacement therapy using the recombinant human GAA (rhGAA) alglucosidase alfa is the only approved treatment available for Pompe disease. While alglucosidase alfa provides some clinical benefits, the infused enzyme shows insufficient uptake into skeletal muscles. This distribution is likely due to suboptimal levels of mannose-6-phosphate (M6P), which is responsible for enzyme internalization and lysosomal targeting. ATB200 is a novel rhGAA with a significantly higher M6P content than alglucosidase alfa. The pharmacological chaperone AT2221 is also utilized to stabilize ATB200 in circulation. We compared the effects of ATB200 co-administered with AT2221 (ATB200/AT2221) to those of alglucosidase alfa in Gaa KO mice. Co-administration of ATB200/AT2221 led to significantly greater glycogen reduction in key muscles. Immunohistochemical analyses suggested that ATB200/AT2221 is more effective than alglucosidase alfa in reducing lysosomal proliferation, enhancing autophagy flux, and repairing damaged muscle fibers. Furthermore, ATB200/AT2221 improved muscle strength compared with alglucosidase alfa. Collectively, these data indicate that ATB200/AT2221 efficiently targets muscle fibers, reverses cellular dysfunction, and improves muscle function. Therefore, ATB200/AT2221 is currently being investigated in the ongoing ATB200-02 clinical trial (NCT02675465) as a potential next-generation treatment for Pompe disease.